Kakajan Komurov, PhD.

Kakajan Komurov, PhD

Maxing out the inherently stressed nature of treatment-resistant breast cancer cells may thwart their ability to find genetic workarounds to treatment, a new study shows.

“We present an alternative strategy for cancer treatment, which is removing cancer cells’ defenses against their own intrinsic stress,” says Kakajan Komurov, PhD, lead author and researcher in the Cancer and Blood Diseases Institute. “Our findings highlight the feasibility of maximizing cell stress by inhibiting adaptive pathways to cause cell death.”

Findings were published May 26, 2015, in Science Signaling. The team focused on an especially hard-to-treat form of breast cancer driven by the HER2-mTOR molecular pathway. Standard treatment for the cancer is combination chemotherapy, including an agent that specifically targets the HER2 gene. But more than half the cases resist the treatment, and the disease progresses.

For this study, researchers used in vitro experimentation with human breast cancer cell lines and extensive computer analysis of genomic data from The Cancer Genome Atlas and International Cancer Genome Consortium.

They searched for non-oncogenic vulnerabilities in breast cancers that overexpress the ERBB2 gene. The authors found that cancers overexpressing ERBB2 have an important survival mechanism for HER2 cancer cells — the endoplasmic reticulum associated degradation pathway, or ERAD.

Researchers then tested a combination treatment that genetically deletes or pharmacologically inhibits ERAD. The treatment killed the HER2-positive breast cancer cells.

They are now testing the experimental regimen in mouse models and plan to begin testing an experimental cancer drug that blocks a component of the ERAD pathway.